Chemokine Expression in Inflamed Adipose Tissue Is Mainly Mediated by NF-κB

Abstract

Immune cell infiltration of expanding adipose tissue during obesity and its role in insulin resistance has been described and involves chemokines. However, studies so far have focused on a single chemokine or its receptor (especially CCL2 and CCL5) whereas redundant functions of chemokines have been described. The objective of this work was to explore the expression of chemokines in inflamed adipose tissue in obesity. Human and mouse adipocytes were analyzed for expression of chemokines in response to inflammatory signal (TNF-α) using microarrays and gene set enrichment analysis. Gene expression was verified by qRT-PCR. Chemokine protein was determined in culture medium with ELISA. Chemokine expression was investigated in human subcutaneous adipose tissue biopsies and mechanism of chemokine expression was investigated using chemical inhibitors and cellular and animal transgenic models. Chemokine encoding genes were the most responsive genes in TNF-α treated human and mouse adipocytes. mRNA and protein of 34 chemokine genes were induced in a dose-dependent manner in the culture system. Furthermore, expression of those chemokines was elevated in human obese adipose tissue. Finally, chemokine expression was reduced by NF-κB inactivation and elevated by NF-κB activation. Our data indicate that besides CCL2 and CCL5, numerous other chemokines such as CCL19 are expressed by adipocytes under obesity-associated chronic inflammation. Their expression is regulated predominantly by NF-κB. Those chemokines could be involved in the initiation of infiltration of leukocytes into obese adipose tissue.

All-trans retinoic acid induces oxidative phosphorylation and mitochondria biogenesis in adipocytes

“…Data were normalized according to the Lowess method, and multiple correction test false discovery rate was applied, then data were fi ltered on the P value ( P < 0.05) for further analyses. Pathway analyses were performed with Metacore (http://www.genego.com/metacore.php), and gene set enrichment analyses (GSEAs) were performed with GSEA software (http://www.broadinstitute.org/gsea) as previously described ( 21,22 ).…”

Vitamin D modulates adipose tissue biology: possible consequences for obesity?

“…Interestingly, Zoico et al recently demonstrated that VD, similarly to 1,25(OH) 2 D, was able to blunt the lipopolysaccharide-mediated pro-inflammatory effect in human adipocytes (37) . Using a microarray approach, we recently demonstrated that 1,25(OH) 2 D was able to downregulate a large set of chemokines (80) induced by inflammatory stimulus (81) in human and murine adipocytes. This effect was accompanied by a reduction of macrophage migration mediated by an adipocyte-conditioned medium (80) .…”

All- trans -retinoic acid represses chemokine expression in adipocytes and adipose tissue by inhibiting NF-κB signaling

“…As previously demonstrated, the expression of several chemokines is upregulated in inflammatory 269 conditions, mainly via the NF-κB signaling pathway in human adipocytes [4], and in 3T3-L1 adipocytes 270 [23]. Since NF-κB activation is central in the induction of chemokines, we next examined whether the effect 271 of ATRA on chemokine production could be mediated through limitation of NF-κB signaling in murine 272 adipocytes.…”

“…Among the soluble factors it produces are the adipokines: these include leptin, 43 adiponectin, tumor necrosis factor-alpha (TNFα), interleukin-6 (IL6), interleukin-1β (IL1β), and 44 chemokines [3]. These cytokines are mainly produced by infiltrating macrophages, although adipocytes 45 play a role [4].…”